RESUMEN
The infiltration and cytotoxicity of chimeric antigen receptor (CAR)-T cells are crucial for effective elimination of solid tumors. While metallo-immunotherapy is a promising strategy that can activate the antitumor immunity, its role in promoting CAR-T cell therapy remains elusive. The first single-element nanomaterial based on chromium nanoparticles (Cr NPs) for cancer photo-metallo-immunotherapy has been reported previously. Herein, an extended study using biodegradable polydopamine as a versatile carrier for these nanoparticles, enabling synergistic CAR-T cell therapy, is reported. The results show that these nanocomposites with or without further encapsulation of the anticancer drug alpelisib can promote the CAR-T cell migration and antitumor effect. Upon irradiation with near-infrared light, they caused mild hyperthermia that can "warm" the "cold" tumor microenvironment (TME). The administration of B7-H3 CAR-T cells to NOD severe combined immunodeficiency gamma mice bearing a human hepatoma or PIK3CA-mutated breast tumor can significantly inhibit the tumor growth after the induction of tumor hyperthermia by the nanocomposites and promote the secretion of serum cytokines, including IL-2, IFN-γ, and TNF-α. The trivalent Cr3+ ions, which are the major degradation product of these nanocomposites, can increase the CXCL13 and CCL3 chemokine expressions to generate tertiary lymphoid structures (TLSs) in the tumor tissues, facilitating the CAR-T cell infiltration.
RESUMEN
Senescence is a cellular response having physiological and reparative functions to preserve tissue homeostasis and suppress tumor growth. However, the accumulation of senescent cells would cause deleterious effects that lead to age-related dysfunctions and cancer progression. Hence, selective detection and elimination of senescent cells are crucial yet remain a challenge. A ß-galactosidase (ß-gal)-activated boron dipyrromethene (BODIPY)-based photosensitizer (compound 1) is reported here that can selectively detect and eradicate senescent cells. It contains a galactose moiety connected to a pyridinium BODIPY via a self-immolative nitrophenylene linker, of which the photoactivity is effectively quenched. Upon interactions with the senescence-associated ß-gal, it undergoes enzymatic hydrolysis followed by self-immolation, leading to the release of an activated BODIPY moiety by which the fluorescence emission and singlet oxygen generation are restored. The ability of 1 to detect and eliminate senescent cells is demonstrated in vitro and in vivo, using SK-Mel-103 tumor-bearing mice treated with senescence-inducing therapy. The results demonstrate that 1 can be selectively activated in senescent cells to trigger a robust senolytic effect upon irradiation. This study breaks new ground in the design and application of new senolytic agents based on photodynamic therapy.
Asunto(s)
Senescencia Celular , Fotoquimioterapia , Fármacos Fotosensibilizantes , Porfobilinógeno , beta-Galactosidasa , beta-Galactosidasa/metabolismo , Senescencia Celular/efectos de los fármacos , Fármacos Fotosensibilizantes/farmacología , Animales , Ratones , Fotoquimioterapia/métodos , Humanos , Porfobilinógeno/análogos & derivados , Porfobilinógeno/farmacología , Porfobilinógeno/química , Compuestos de Boro/farmacología , Compuestos de Boro/química , Modelos Animales de Enfermedad , Línea Celular TumoralRESUMEN
Manipulation of cell-cell interactions via cell surface modification is crucial in tissue engineering and cell-based therapy. To be able to monitor intercellular interactions, it can also provide useful information for understanding how the cells interact and communicate. We report herein a facile bioorthogonal strategy to promote and monitor cell-cell interactions. It involves the use of a maleimide-appended tetrazine-caged boron dipyrromethene (BODIPY)-based fluorescent probe and a maleimide-substituted bicyclo[6.1.0]non-4-yne (BCN) to modify the membrane of macrophage (RAW 264.7) and cancer (HT29, HeLa, and A431) cells, respectively, via maleimide-thiol conjugation. After modification, the two kinds of cells interact strongly through inverse electron-demand Diels-Alder reaction of the surface tetrazine and BCN moieties. The coupling also disrupts the tetrazine quenching unit, restoring the fluorescence emission of the BODIPY core on the cell-cell interface, and promotes phagocytosis. Hence, this approach can promote and facilitate the detection of intercellular interactions, rendering it potentially useful for macrophage-based immunotherapy.
Asunto(s)
Compuestos de Boro , Comunicación Celular , Colorantes Fluorescentes , Humanos , Compuestos de Boro/química , Ratones , Animales , Colorantes Fluorescentes/química , Células RAW 264.7 , Maleimidas/química , Células HeLaRESUMEN
An acetal-linked dimeric phthalocyanine has been synthesised and immobilised on the surface of gold nanobipyramids. The resulting nanocomposite serves as a highly sensitive probe for intracellular pH through its acid-responsive fluorescence and surface-enhanced Raman scattering signals. The phthalocyanine units released in the acidic intracellular environment can also effectively eliminate the cancer cells upon light irradiation, rendering this simple fabricated nanosystem a bimodal and bifunctional theranostic agent.
Asunto(s)
Oro , Indoles , Isoindoles , Fotoquimioterapia , Indoles/química , Indoles/efectos de la radiación , Oro/química , Humanos , Concentración de Iones de Hidrógeno , Fotoquimioterapia/métodos , Nanopartículas del Metal/química , Nanopartículas del Metal/efectos de la radiación , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/efectos de la radiación , Espectrometría Raman/métodos , Neoplasias , Dimerización , Línea Celular TumoralRESUMEN
As an effective and non-invasive treatment modality for cancer, photodynamic therapy (PDT) has attracted considerable interest. With the recent advances in the photosensitizing agents, the fiber-optic systems, and other aspects, its application is extended to a wide range of superficial and localized cancers. However, for the few clinically used photosensitizers, most of them suffer from the drawback of causing prolonged photosensitivity after the treatment. As a result, post-PDT management is also a crucial issue. Herein, a facile bioorthogonal approach is reported that can effectively suppress this common side effect of PDT in nude mice. It involves the use of an antidote that contains a black-hole quencher BHQ-3 conjugated with a bicyclo[6.1.0]non-4-yne (BCN) moiety and a tetrazine-substituted boron dipyrromethene-based photosensitizer. By using tumor-bearing nude mice as an animal model, it is demonstrated that after PDT with this photosensitizer, the administration of the antidote can effectively quench the photodynamic activity of the residual photosensitizer by bringing the BHQ-3 quencher close to the photosensitizing unit through a rapid click reaction. It results in substantial reduction in skin damage upon light irradiation. The overall results demonstrate that this simple and facile strategy can provide an effective means for minimizing the photosensitivity after PDT.
Asunto(s)
Neoplasias , Fotoquimioterapia , Animales , Ratones , Fármacos Fotosensibilizantes/uso terapéutico , Fotoquimioterapia/métodos , Antídotos , Ratones Desnudos , Neoplasias/tratamiento farmacológicoRESUMEN
Senescent cells have become an important therapeutic target for many age-related dysfunctions and diseases. We report herein a novel nanophotosensitizing system that is responsive to the senescence-associated ß-galactosidase (ß-gal) for selective detection and elimination of these cells. It involves a dimeric zinc(II) phthalocyanine linked to a ß-galactose unit via a self-immolative linker. This compound can self-assemble in aqueous media, forming stable nanoscale particles in which the phthalocyanine units are stacked and self-quenched for fluorescence emission and singlet oxygen production. Upon internalization into senescent HeLa cells, these nanoparticles interact with the overproduced senescence-associated ß-gal inside the cells to trigger the disassembly process through enzymatic cleavage of the glycosidic bonds, followed by self-immolation to release the photoactive monomeric phthalocyanine units. These senescent cells can then be lit up with fluorescence and eliminated through the photodynamic action upon light irradiation with a half-maximal inhibitory concentration of 0.06 µM.
Asunto(s)
Fotoquimioterapia , Humanos , Células HeLa , Fluorescencia , beta-Galactosidasa , Indoles/farmacología , Indoles/química , Senescencia CelularRESUMEN
A water-soluble 1,2,4,5-tetrazine-substituted carbon-dipyrromethene (C-DIPY) was synthesized from the previously reported carbonyl pyrrole dimer through a two-step procedure. Owing to the presence of a tetrazine moiety, the fluorescence emission of this compound was largely quenched in phosphate-buffered saline at pHâ 7.4. Upon addition of a bicyclo[6.1.0]non-4-yne (BCN) derivative, the tetrazine-based quenching component of the compound was disrupted through the inverse electron-demand Diels-Alder reaction to restore the fluorescence in up to 6.6-fold. This bioorthogonal activation was also demonstrated using U-87 MG human glioblastoma cells, in which the fluorescence intensity of this C-DIPY could be enhanced by 8.7-fold upon post-incubation with the BCN derivative. The results showed that this tetrazine-caged C-DIPY can serve as a bioorthogonally activatable fluorescent probe for bioimaging. The compound, however, was found to reside preferentially in the lysosomes instead of the mitochondria of the cells as predicted based on its cationic character, which could be attributed to its energy-dependent endocytic cellular uptake pathway, for which lysosomes are the end station.
Asunto(s)
Colorantes Fluorescentes , Compuestos Heterocíclicos , Humanos , Colorantes Fluorescentes/química , Reacción de Cicloadición , PorfobilinógenoRESUMEN
The utilisation of enzymes as stimuli can activate theranostic agents in a highly specific manner. We report herein a far-red-absorbing boron dipyrromethene-based photosensitiser that is responsive towards the cancer-associated human NAD(P)H:quinone oxidoreductase 1, enabling the controlled restoration of photodynamic activity for selective elimination of cancer cells.
Asunto(s)
Fotoquimioterapia , Fármacos Fotosensibilizantes , Humanos , Fármacos Fotosensibilizantes/farmacología , NAD , NAD(P)H Deshidrogenasa (Quinona) , QuinonasRESUMEN
Photodynamic therapy and sonodynamic therapy are two highly promising modalities for cancer treatment. The latter holds an additional advantage in deep-tumor therapy owing to the deep penetration of the ultrasonic radiation. The therapeutic efficacy depends highly on the photo/ultrasound-responsive properties of the sensitizers as well as their tumor-localization property and pharmacokinetics. A novel nanosensitizer system based on a polymeric phthalocyanine (pPC-TK) is reported herein in which the phthalocyanine units are connected with cleavable thioketal linkers. Such polymer could self-assemble in water forming nanoparticles with a hydrodynamic diameter of 48 nm. The degradable and flexible thioketal linkers could effectively inhibit the π-π stacking of the phthalocyanine units, rendering the resulting nanoparticles an efficient generator of reactive oxygen species upon light or ultrasonic irradiation. The nanosensitizer could be internalized into cancer cells readily, inducing cell death by efficient photodynamic and sonodynamic effects. The potency is significantly higher than that of the monomeric phthalocyanine (PC-4COOH). The nanosensitizer could also effectively inhibit the growth of tumor in liver tumor-bearing mice by these two therapies without causing noticeable side effects. More importantly, it could also retard the growth of a deep-located orthotopic liver tumor in vivo by sonodynamic therapy.
Asunto(s)
Neoplasias Hepáticas , Nanopartículas , Fotoquimioterapia , Terapia por Ultrasonido , Animales , Ratones , Fotoquimioterapia/métodos , Isoindoles , Indoles/farmacología , Nanopartículas/uso terapéutico , Polímeros , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Guest Editors Pui-Chi Lo, Dennis Ng, Ravindra Pandey, and Petr Zimcik introduce the Special Collection on Photodynamic Therapy and give an overview of the developments and challenges in this exciting field.
Asunto(s)
Neoplasias , Fotoquimioterapia , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
A ß-galactosidase-responsive photosensitiser has been designed and synthesised. It contains a galactosyl substrate, a boron dipyrromethene-based photosensitising unit and a black hole quencher 2 connected via an AB2-type self-immolative linker. This novel photosensitiser can be selectively activated by the senescence-associated ß-galactosidase in senescent cells, leading to restoration in fluorescence emission and effective killing of the cells via photodynamic action.
Asunto(s)
Galactosidasas , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/farmacología , beta-Galactosidasa , Línea Celular Tumoral , Senescencia CelularRESUMEN
An advanced photodynamic molecular beacon (PMB) was designed and synthesized, in which a distyryl boron dipyrromethene (DSBDP)-based photosensitizer and a Black Hole Quencher 3 moiety were connected via two peptide segments containing the sequences PLGVR and GFLG, respectively, of a cyclic peptide. These two short peptide sequences are well-known substrates of matrix metalloproteinase-2 (MMP-2) and cathepsin B, respectively, both of which are overexpressed in a wide range of cancer cells either extracellularly (for MMP-2) or intracellularly (for cathepsin B). Owing to the efficient Förster resonance energy transfer between the two components, this PMB was fully quenched in the native form. Only upon interaction with both MMP-2 and cathepsin B, either in a buffer solution or in cancer cells, both of the segments were cleaved specifically, and the two components could be completely separated, thereby restoring the photodynamic activities of the DSBDP moiety. This PMB could also be activated in tumors, and it effectively suppressed the tumor growth in A549 tumor-bearing nude mice upon laser irradiation without causing notable side effects. In particular, it did not cause skin photosensitivity, which is a very common side effect of photodynamic therapy (PDT) using conventional "always-on" photosensitizers. The overall results showed that this "double-locked" PMB functioned as a biological AND logic gate that could only be unlocked by the coexistence of two tumor-associated enzymes, which could greatly enhance the tumor specificity in PDT.
Asunto(s)
Fotoquimioterapia , Ratones , Animales , Metaloproteinasa 2 de la Matriz , Catepsina B , Ratones Desnudos , Línea Celular Tumoral , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/química , Péptidos/químicaRESUMEN
Pt(II)-BODIPY complexes combine the chemotherapeutic activity of Pt(II) with the photocytotoxicity of BODIPYs. Additional conjugation with targeting ligands can boost the uptake by cancer cells that overexpress the corresponding receptors. We describe two Pt(II) triangles, 1 and 2, built with pyridyl BODIPYs functionalized with glucose (3) or triethylene glycol methyl ether (4), respectively. Both 1 and 2 showed higher singlet oxygen quantum yields than 3 and 4, due to the enhanced singlet-to-triplet intersystem crossing. To evaluate the targeting effect of the glycosylated derivative, in vitro experiments were performed using glucose transporter 1 (GLUT1)-positive HT29 and A549 cancer cells, and noncancerous HEK293 cells as control. Both 1 and 2 showed higher cellular uptake than 3 and 4. Specifically, 1 was selective and highly cytotoxic toward HT29 and A549 cells. The synergistic chemo- and photodynamic behavior of the metallacycles was also confirmed. Notably, 1 exhibited superior efficacy toward the cisplatin-resistant R-HepG2 cells.
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Antineoplásicos , Fotoquimioterapia , Humanos , Antineoplásicos/farmacología , Células HEK293 , Fármacos Fotosensibilizantes/farmacologíaRESUMEN
Invited for this month's cover is the group of Prof. Dennis K. P. Ng at The Chinese University of Hong Kong. The cover picture shows the selective internalization of molecules of a di-galactosyl zinc(II) phthalocyanine into a cancer cell. Upon light irradiation, these molecules are excited and interact with the endogenous oxygen to generate highly reactive singlet oxygen, which oxidatively damages the cellular components, leading to cell death eventually. More information can be found in the Research Article by Dennisâ K.â P. Ng, and co-workers.
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Compuestos Organometálicos , Fotoquimioterapia , Humanos , Fármacos Fotosensibilizantes/farmacología , Zinc , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/metabolismoRESUMEN
We report herein a versatile and efficient bioorthogonal strategy to actualise targeted delivery and site-specific activation of photosensitisers for precise antitumoural photodynamic therapy. The strategy involved the use of an isonitrile-caged distyryl boron dipyrromethene-based photosensitiser, labelled as NC-DSBDP, of which the photoactivities could be specifically activated upon conversion of the meso ester substituent to carboxylate initiated by the [4 + 1] cycloaddition with a tetrazine derivative. By using two tetrazines conjugated with a galactose moiety or the GE11 peptide, labelled as gal-Tz and GE11-Tz, we could selectively label the cancer cells overexpressed with the asialoglycoprotein receptor and the epidermal growth factor receptor respectively. Upon encountering the internalised NC-DSBDP, these tetrazines triggered the "ester-to-carboxylate" transformation of this compound, activating its fluorescence and reactive oxygen species generation inside the target cells. The bioorthogonal activation was also demonstrated in vivo, leading to effective photo-eradication of the tumour in nude mice.
Asunto(s)
Compuestos Heterocíclicos , Neoplasias , Fotoquimioterapia , Animales , Ratones , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/química , Ratones Desnudos , Compuestos Heterocíclicos/química , Neoplasias/tratamiento farmacológicoRESUMEN
A series of di-α-substituted zinc(II) phthalocyanines with different number of galactose moieties, ranging from 1 to 8, namely Pc-galn (n=1, 2, 4, and 8) were designed and synthesized. The synthesis involved the copper-catalyzed azide-alkyne cycloaddition reaction of a mono- or dialkynyl zinc(II) phthalocyanine with an acetyl-protected galactosyl azide or its dendritic derivative with four acetyl-protected galactosyl groups, followed by removal of the acetyl protecting groups via alkaline hydrolysis. In N,N-dimethylformamide, these oligogalactosyl phthalocyanines were non-aggregated as shown by the strong Q-band absorption and fluorescence emission. Owing to the di-α-substitution, they also behaved as efficient singlet oxygen generators upon light irradiation with a singlet oxygen quantum yield of 0.84. The spectroscopic and photophysical properties were not affected by the number of galactosyl units. In contrast, the compounds became significantly aggregated and quenched in phosphate-buffered saline. Their cellular uptake was then studied using a range of cell lines, which generally followed the order Pc-gal1 >Pc-gal2 ≈Pc-gal4 >Pc-gal8 . Interestingly, the di-galactosyl analogue exhibited selective uptake against HeLa human cervical carcinoma cells through an energy-dependent pathway instead of the expected asialoglycoprotein receptor. Upon light irradiation, it could effectively kill the cells with a half-maximal inhibitory concentration of 0.58â µM.
Asunto(s)
Fármacos Fotosensibilizantes , Oxígeno Singlete , Humanos , Fármacos Fotosensibilizantes/química , Oxígeno Singlete/metabolismo , Zinc/química , Azidas , Células HeLaRESUMEN
Targeted delivery and specific activation of photosensitizers can greatly improve the treatment outcome of photodynamic therapy. To this end, we report herein a novel dual receptor-mediated bioorthogonal activation approach to enhance the tumor specificity of the photodynamic action. It involves the targeted delivery of a biotinylated boron dipyrromethene (BODIPY)-based photosensitizer, which is quenched in the native form by the attached 1,2,4,5-tetrazine unit, and an epidermal growth factor receptor (EGFR)-targeting cyclic peptide conjugated with a bicycle[6.1.0]non-4-yne moiety. Only for cancer cells that overexpress both the biotin receptor and EGFR, the two components can be internalized preferentially where they undergo an inverse electron-demand Diels-Alder reaction, leading to restoration of the photodynamic activity of the BODIPY core. By using a range of cell lines with different expression levels of these two receptors, we have demonstrated that this stepwise "deliver-and-click" approach can confine the photodynamic action on a specific type of cancer cells.
Asunto(s)
Fotoquimioterapia , Compuestos de Boro/farmacología , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Receptores ErbBRESUMEN
A multifunctional photodynamic molecular beacon (PMB) has been designed and synthesized which contains an epidermal growth factor receptor (EGFR)-targeting cyclic peptide and a trimeric phthalocyanine skeleton in which the three zinc(II) phthalocyanine units are each substituted with a glutathione (GSH)-responsive 2,4-dinitrobenzenesulfonate (DNBS) quencher and are linked via two cathepsin B-cleavable GFLG peptide chains. This tailor-made conjugate is fully quenched in the native form due to the photoinduced electron transfer effect of the DNBS moieties and the self-quenching of the phthalocyanine units. It can target the EGFR overexpressed in cancer cells, and after receptor-mediated endocytosis, it can be activated selectively by the co-existence of intracellular GSH and cathepsin B, both of which are also overproduced in cancer cells, in terms of fluorescence emission and singlet oxygen generation. The cell-selective behavior of this PMB has been demonstrated using a range of cancer cells with different expression levels of EGFR, while the stimuli-responsive properties have been studied both inâ vitro and in various aqueous media. The overall results show that this advanced PMB, which exhibits several levels of control of the tumor specificity, is a promising photosensitizer for precise antitumoral photodynamic therapy.
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Neoplasias , Fotoquimioterapia , Catepsina B/uso terapéutico , Línea Celular Tumoral , Dinitrofluorobenceno/análogos & derivados , Receptores ErbB , Glutatión/química , Humanos , Indoles/química , Neoplasias/patología , Péptidos/uso terapéutico , Péptidos Cíclicos/uso terapéutico , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Oxígeno Singlete/químicaRESUMEN
Photodynamic therapy (PDT) represents a promising treatment modality for a range of cancers and other non-malignant diseases due to its non-invasive nature arising from the light-dependent activation. However, PDT has not been the first-line treatment of cancer thus far as a consequence of, among others, the lack of effective transport and activation strategies, and the undesired side effect caused by skin photosensitisation induced by the "always on" photosensitisers. To overcome this "Achilles' heel", we present herein a non-covalent approach to construct a one-component dynamic supramolecular nanophotosensitising system based on a carefully designed porphyrin. The control of the photoactivities of the resulting supramolecular fibres lies in the spatiotemporal control of the monomer-polymer equilibrium. Both the thermodynamics and kinetics of this nanosystem have been carefully studied by different techniques. Moreover, in vitro and in vivo studies have also been performed, showing that these supramolecular aggregates exhibit facile cell internalisation and progressive disassembly after being endocyted by targeted cells, leading to activation of the photosensitising units and eventually cell death and tumour eradication under photoirradiation.
Asunto(s)
Nanofibras , Neoplasias , Fotoquimioterapia , Porfirinas , Humanos , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes , Porfirinas/farmacología , Porfirinas/uso terapéuticoRESUMEN
Delivery of functional proteins into the intracellular space has been a challenging task that could lead to a myriad of therapeutic applications. We report herein a novel bioconjugation strategy for enzyme modification and selective delivery into cancer cells for lock-and-key-type activation of photosensitizers. Using a bifunctional linker containing a bis(bromomethyl)phenyl group and an o-phthalaldehyde moiety, it could induce cyclization of the peptide sequence Ac-NH-CRGDfC-CONH2 through site-specific dibenzylation with the two cysteine residues and further coupling with ß-galactosidase via the phthalaldehyde-amine capture reaction. This facile two-step one-pot procedure enabled the preparation of cyclic RGD-modified ß-galactosidase readily, which could be internalized selectively into αvß3 integrin-overexpressed cancer cells. Upon encountering an intrinsically quenched distyryl boron dipyrromethene-based photosensitizer conjugated with a galactose moiety through a self-immolative linker inside the cells, the extrinsic enzyme induced specific cleavage of the ß-galactosidic bond followed by self-immolation to release an activated derivative, thereby restoring the photodynamic activities and causing cell death effectively. The high specificity of this extrinsic enzyme-activated photosensitizing system was also demonstrated in vivo using nude mice bearing an αvß3 integrin-positive U87-MG tumor. The specific activation at the tumor site resulted in lighting up and complete eradication of the tumor upon laser irradiation, while by using the native ß-galactosidase, the effects were largely reduced. In contrast to the conventional activation using intrinsic enzymes, this extrinsic enzyme activatable approach can further minimize the nonspecific activation toward precisive photodynamic therapy.